Interpretive Handbook

Test
89553 :
Succinate Dehydrogenase (SDH) Subunit D Gene Analysis

Succinate dehydrogenase (SDH) is a mitochondrial membrane-bound enzyme complex consisting of 4 subunits: SDHA, SDHB, SDHC, and SDHD. SDH is an oxidoreductase that catalyzes the oxidation of succinate to fumarate (tricarboxylic acid cycle function) and the reduction of ubiquinone to ubiquinol (respiratory chain function).

Heterozygous mutations/deletions of SDHB, SDHC, or SDHD result in a high life-time penetrance autosomal dominant tumor syndrome. Patients have only 1 functioning germline copy of the affected SDH subunit gene. When the second, intact copy is somatically lost or mutated in target tissues, tumors develop. Sympathetic and parasympathetic ganglia are preferentially affected, resulting in development of paragangliomas (PGL) or pheochromocytomas (PC). PGLs might include parasympathetic ganglia (neck and skull-base) or sympathetic ganglia (paravertebral sympathetic chain from neck to pelvis). PCs can involve 1 or both adrenal glands. Almost all PCs overproduce catecholamines, resulting in hypertension with a predilection for hypertensive crises. About 20% of PGL, mostly intra-abdominal, also secrete catecholamines. PGLs in the neck do not usually produce catecholamines. SDH-associated PGLs and PCs are typically benign; however, malignancy has been described in a minority of patients (especially in patients with SDHB mutations). In addition, because of the germline presence of the mutation/deletion, new primary tumors might occur over time in the various target tissues. Finally, tumors unrelated to chromaffin tissues, namely renal cell carcinoma (RCC) and gastrointestinal stromal tumors (GIST), affect some patients.

Collectively, heterozygous germline mutations/deletions of SDHB, SDHC, or SDHD are found in 30% to 50% of apparently sporadic PGL cases and can be confirmed in >90% of clinically hereditary cases. The corresponding figures are 1% to 10% and 20% to 30% for outwardly sporadic PC and seemingly inherited PC, respectively. The prevalence of SDHD mutations/deletions is higher than that of SDHB, which in turn exceeds the figures for SDHC. SDHB and SDHC mutations show classical autosomal dominant inheritance, while SDHD mutations show a modified autosomal dominant inheritance with chiefly paternal transmission, suggesting maternal imprinting (the molecular correlate of which remains unknown). SDHB is most strongly associated with PGL (usually functioning), but adrenal PCs also occur, as do occasional GISTs and RCCs. SDHD shows a disease spectrum similar to SDHB, except head and neck PGLs are more frequent than in SDHB, while functioning or malignant PGLs/PCs and GISTs are less common. SDHC has thus far been mainly associated with PGLs of skull base and neck. Abdominal/functioning PGLs or PCs are uncommonly seen in patients with SDHC mutations and GISTs are very rare. However, there is limited certainty about the SDHC genotype-phenotype correlations, as the reported case numbers are low.

Genetic testing for SDHB, SDHC, and SDHD germline mutations and deletions is highly accurate in identifying affected patients and pre-symptomatic individuals. It is advocated in all patients who present with PGL. Accurate diagnosis assists in designing optimal follow-up strategies, since the rate of new/recurrent tumors is much higher in patients with SDH mutations or deletions than in true sporadic cases.

Screening for mutations in SDH genes is not currently advocated for sporadic adrenal PC, but is gaining in popularity, often alongside tests for mutations of other predisposing genes, RET (multiple endocrine neoplasia type 2, MEN2), VHL (von Hippel-Lindau syndrome), and NF1 (neurofibromatosis type 1). Seemingly familial PC cases that do not have an established diagnosis of a defined familial tumor syndrome should be screened for SDH gene mutations, along with screening of the other predisposing genes listed above.

In order to minimize the cost of genetic testing, the clinical pattern of lesions in PGL and PC patients might be used to determine the order in which the 3 disease-associated SDH genes are tested. Genetic diagnosis of index cases allows targeted pre-symptomatic testing of relatives.

All detected alterations will be evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants will be classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Rare unknown polymorphisms in primer or probe binding sites can rarely result in allelic drop-out and false-negative genetic tests.

The current test does not examine the promoters, other gene regulatory elements, or most of the intronic portions of the SDHD gene. It is unknown what the impact of this on detection rates is. Based on observations in other genetic disorders, it is generally believed that <5% of disease-causing mutations occur in these regions.

This method detects point mutations and small insertions and deletions, but does not detect large deletions. For detection of large deletions order SDHDD / Succinate Dehydrogenase (SDH) Gene, Deletion Detection.

There may be (several) other, as yet unidentified, genes that can cause a phenotypically similar picture as succinate dehydrogenase (SDH) mutations/deletions.

Collectively, the above causes, along with various other preanalytical and analytical problems that are not unique to genetic testing (eg, specimen mix up), probably account for the estimated false-negative rate of <10% (likely <5%) that is observed with genetic SDH testing.